Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationships

Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10878-82. doi: 10.1073/pnas.91.23.10878.

Abstract

Hyperinsulinemia, loss of glucose-stimulated insulin secretion (GSIS), and peripheral insulin resistance coexist in non-insulin-dependent diabetes mellitus (NIDDM). Because free fatty acids (FFA) can induce these same abnormalities, we studied their role in the pathogenesis of the NIDDM of obese Zucker diabetic fatty (ZDF-drt) rats from 5 weeks of age (before the onset of hyperglycemia) until 14 weeks. Two weeks prior to hyperglycemia, plasma FFA began to rise progressively, averaging 1.9 +/- 0.06 mM at the onset of hyperglycemia (P < 0.001 vs. controls). At this time GSIS was absent and beta-cell GLUT-2 glucose transporter was decreased. The triacylglycerol content of prediabetic islets rose to 10 times that of controls and was correlated with plasma FFA (r = 0.825; P < 0.001), which, in turn, was correlated with the plasma glucose concentration (r = 0.873; P < 0.001). Reduction of hyperlipacidemia to 1.3 +/- 0.07 mM by pair feeding with lean littermates reduced all beta-cell abnormalities and prevented hyperglycemia. Normal rat islets that had been cultured for 7 days in medium containing 2 mM FFA exhibited increased basal insulin secretion at 3 mM glucose, and first-phase GSIS was reduced by 68%; in prediabetic islets, first-phase GSIS was reduced by 69% by FFA. The results suggest a role for hyperlipacidemia in the pathogenesis of NIDDM; resistance to insulin-mediated antilipolysis is invoked to explain the high FFA despite hyperinsulinemia, and sensitivity of beta cells to hyperlipacedemia is invoked to explain the FFA-induced loss of GSIS.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adipocytes / pathology*
  • Animals
  • Diabetes Mellitus, Type 2 / pathology*
  • Energy Intake
  • Fatty Acids / metabolism
  • Fatty Acids, Nonesterified / blood
  • Female
  • Islets of Langerhans / pathology*
  • Male
  • Rats
  • Rats, Mutant Strains
  • Rats, Wistar
  • Triglycerides / metabolism

Substances

  • Fatty Acids
  • Fatty Acids, Nonesterified
  • Triglycerides